Society has long misunderstood these spineless swimmers. Now they could unlock the keys to regeneration.

Hiroshima’s downtown is a garden of modern architecture interspersed with
swaths of lovely green parks. In the center is a single structure, in
ruins, capped by a skeleton of curved iron. This is the Atomic Bomb Dome,
located at the destruction’s epicenter, the sole building that managed to
remain standing amid the massive force that flattened everything else for
miles in all directions. It is an astonishing memorial to both our capacity
for horrifying devastation and our awesome resilience. The dome sits along
the side of one of six tidal streams that flow through Hiroshima.

In the murky, green water, thousands — maybe hundreds of thousands — of
pale pink disks, a flood of jellyfish parade by as I observe. Juxtaposed
with the dome, the endless stream of jellyfish seems to square off nature’s
power against our own, a battle as old as civilization that continues to
play out in the decisions we make today. The milky creatures pulse slowly,
slower than my heartbeat, which drops as I watch. The movements of their
bells trailing gossamer tentacles are like millions of eyelashes blinking
open and closed and open again, giving me a feeling that these alien
animals could peer deep into the soul of the sea. I find it impossible to
fathom the source of this endless river of life. The jellies continue to
flow by for as long as I stand there.

Monster, Goddess

The technical name for the stage of a jellyfish’s life when it swims freely
in the seas is medusa, a moniker shared with the ancient Greek mythological
monster. Medusa is famous for her horrible face, which turned men to stone,
and her wild locks of hissing snakes. It’s not hard to see similarities.

But dig deeper into the story of Medusa, and what you find is not at all a
monster, but a victim whose story has been misunderstood. Medusa was born
to two ancient marine deities and, according to Ovid, was stunningly
gorgeous. She served the goddess Athena in her temple. Some say Medusa was
a temptress and lured Poseidon in. Others say Poseidon couldn’t control
himself. As in too many cases, it depends who’s telling the story. Since I
am: He raped her, right there in Athena’s temple.

Because it was ancient Greece, Medusa had little recourse. Athena went into
a rage that her temple had been defiled, turned Medusa into a hideous
monster, and kicked her out. Medusa — who deserved at least a shoulder to
cry on, if not justice in a court — instead banished herself to a remote
island, frightened and deformed. Imagine her disgust, shock and horror to
find that she was also pregnant with her assailant’s offspring. To complete
the tragedy, the man always regarded as a hero, Perseus, arrived. Using the
tricks of the gods — an invisibility cloak, winged sandals, and a mirrored
shield — he snuck up on Medusa. She never had a chance. He murdered her.

Like their mythical namesake, jellyfish are also awash in
misunderstanding. They have no centralized brain, but they see and feel
and react to their environment in complex ways. Their body form looks
simple, yet their swimming ability is the most economical in the animal
kingdom. We know them in their swimming medusa form, but they live as much
or more of their lives as a mysterious tiny tube called a polyp, planted on
the underside of a rock.

They wash ashore in hordes, and they dominate the deepest depths of our
planet, supporting entire ecosystems. And still, scientists cannot predict
where and when to find them. To some, jellyfish symbolize the monster — not
only in their potentially lethal sting, but also in a more global sense, as
a symptom of ecosystem demise. At the same time, jellyfish are utterly,
breathtakingly beautiful.

Perhaps the extraordinary creativity of this balance, this surprising
ability to exist in the space between monster and goddess, is why jellyfish
resonate so deeply within all of us. Perhaps the story of jellyfish is
really about our own possibilities.

Aging Reversed

The story of the immortal jellyfish starts in 1988. A marine biology
student had collected a minuscule bell-shaped medusa with a smattering of
thin tentacles and a pinkish chandelier of gonads from shallow water near
Genoa on Italy’s northwest coast. One Friday, he left the medusa in a bowl
of seawater, forgetting to put it back in the refrigerator for the weekend.
When he returned Monday, the medusa was missing. But it hadn’t completely
disappeared. The bowl held a polyp.

That was odd. Jellyfish are known to cycle through life in order: A
fertilized egg grows into a furry Tic Tac-shaped larva, which metamorphoses
into a polyp, which buds into swimming medusas, which produce eggs or sperm
and then die (See “Turritopsis Life Cycle” below). But there
hadn’t been enough time for the medusa in the bowl of seawater to spawn,
grow into a larva, and end up a polyp over the weekend. Those
transformations take weeks. In order for a polyp to end up in the bowl of
seawater, the jellyfish must have reverse-aged, like Benjamin Button,
morphing backward through its life cycle from medusa to polyp.

Ordinarily, jellyfish are born from eggs and grow into larvae, which morph into polyps before becoming free-swimming medusa. Turritopsis isn’t bound by that life cycle. If you skewer a medusa, it can turn back into a polyp.

Alison Mackey/Discover and Jay Smith

It has been known for centuries that jellyfish don’t always color inside
the lines when it comes to their life cycles. Some species skip the polyp
stage, going straight from larvae, called planula, to medusa. Many skip the
medusa stage, remaining a polyp through old age. Polyps can bud from other
polyps. Medusas can bud from the underbellies of other medusas. Despite all
the plasticity in the jellyfish life cycle, scientists had believed that
there was a limit, that once a medusa reached reproductive age, those sorts
of unusual transformations would be impossible. Once an animal became
mature enough to produce eggs or sperm, it was thought, the only option was
to spawn and die — that is, until the jellyfish left sitting on the counter
for the weekend rejuvenated itself.

Unbaking a Pretzel

Stefano Piraino of the University of Salento in Italy discovered a colony
of this same immortal jellyfish, called Turritopsis, near his lab in Lecce
— and as with Ponce de León’s Fountain of Youth, its exact location remains
a bit of a mystery to the general public. But Piraino knows where it is,
and it has allowed him to very carefully study the life cycle of the
animal. In the lab, Piraino and his collaborators watched the jellyfish
morph from polyp to medusa and back to polyp and back to medusa and back to
polyp, without ever going through the spawn-and-die part of their lives.

Jellyfish larvae typically morph into anchored polyps, shown here, before they mature into free-swimming medusa. But some jellies skip life stages, or just stay a polyp forever.

Stefano Piraino

“This process would be hardly more remarkable if a butterfly were able to
revert to its caterpillar stage. It must be considered a true
metamorphosis, but in the opposite direction to larval metamorphosis,” they
wrote.

For all intents and purposes, these jellyfish were immortal.

Still, Piraino said he always cautions people that Turritopsis can be
killed and do die, by infection or predation, among other possibilities.
“If they were truly immortal, the ocean would be completely full of
Turritopsis, and we don’t see that,” he says. But at least theoretically,
jellyfish can morph forward and backward through their life cycle forever.
One scientist in Japan has kept the same turritopsis in culture in his lab
for dozens of years.

Recently, we learned that this proclivity for agelessness might not be
constrained to just one species of small jellyfish.

Turritopsis is a truly tiny species. Most medusa, shown here, are eaten in the wild, rendering their “immortality” worthless.

Ian Gavan/Getty Images

In 2016, a Chinese graduate student, Jinru He, neglected the medusa of
another species, the moon jellyfish. After a couple of days, the medusa
sank to the floor of the tank and stopped moving. The animal broke into
pieces, and any normal person would have considered it dead and washed it
down the drain. But not this scientist; he kept watching. After a couple of
months, the detritus of the medusa began to reconstitute itself like a
phoenix rising from its ashes. Tentacles emerged. A mouth formed.
Eventually, perfectly healthy polyps sprang to life from the medusa
carcass. Rather than simply die, the jellyfish had seemingly reversed its
life cycle, going from the degraded medusa backward to the polyp stage.

Like animals, individual cells proceed through a life cycle. All types of
cells are born as generic stem cells, like a lump of dough with a lot of
potential. Specific genes turn on and off inside each stem cell, changing
it into a muscle cell, a skin cell, or a nerve cell in the same way a baker
molds the dough into a pizza crust, a loaf of bread or a pretzel. You can’t
turn a pretzel into a pizza any longer. Likewise, a muscle cell can’t morph
into a nerve cell.

Tapping Into Immortality

Piraino wanted to understand what happens to the cells inside the
jellyfish’s body when it goes through its reverse aging. Was there a limit
to the life of a cell for Turritopsis? Are Turritopsis cells ever fully
baked? The answer — incredibly — seems to be no.

Normally, the genetic switches that control the transformation of an embryo
into a larva or a larva into a polyp are switched on in an order that is
irreversible, “but Turritopsis cells can hit the rewind button,” Piraino
explained.

When the Turritopsis medusa rejuvenates, muscle cells, for example, turn
certain genes on or off, essentially unbaking the cells and reverting them
to doughlike stem cells. Then those stem cells re-form into new and
different cells in the polyp.

Turritopsis can act like a shape-shifter. Their stem cells can develop into specialized cells, then move back to a simpler state.

Stefano Piraino

The idea that fully cooked cells can become stem cells again has enormous
and tantalizing possibilities for medical research. If we could hit the
rewind button in our cells, we could open the door to all kinds of
treatments for diseases in which cells have gone awry, ailments like
Parkinson’s disease and cancer. “Cancer is cell proliferation without
rules,” Piraino said. “It is uncontrolled growth. There is no plan for what
to do with the new cells.” But in Turritopsis, the reprogramming of one
cell into another kind of cell “is part of a controlled pathway.” We just
need to learn what those controls are.

Maria Pia Miglietta of Texas A&M University’s marine lab is one of
Piraino’s collaborators on Turritopsis. In 2009, she discovered that the
Turritopsis living off Japan, Panama, Florida, Spain and Italy were all
nearly identical genetically and classified them as the same species. So
while the oceans are not filled with the immortal jellyfish, she confirmed
that they have spread worldwide.

Miglietta found that the conduit for the spread was us, through ships’
ballast water. Unlike some other species, the immortal jellyfish pose
little threat to the ecosystem because it is so small — or to us, because
its sting isn’t painful. However, the ability to flip back and forth
between a medusa and a polyp probably allowed it to withstand the stressful
conditions in a boat’s hull and likely helped the jellyfish achieve its
global range.

Cell Instructions

Miglietta’s work on Turritopsis genes was still in progress when I met with
her in Texas, but the plan she’s following originated with two Japanese
biologists, Shinya Yamanaka and his student Kazutoshi Takahashi. In the
early 2000s, they injected mouse skin cells with between four and seven
pieces of protein called transcription factors. Transcription factors
attach to DNA and control which genes are flipped on. The Japanese
scientists discovered that the presence of just those few proteins had the
power to transform skin cells backward — to the lump-of-dough stem-cell
stage. And from those stem cells, scientists were able to grow nerve cells,
blood cells and heart muscle cells. For this rule-shattering work, Yamanaka
received the Nobel Prize in 2012.

One major roadblock, Miglietta told me, is that most of the work on
transcription factors has been done on cells grown in a culture dish. In
the real world, animal cells exist in the ecosystem of bodies. They are in
constant conversation with nearby cells, exchanging molecular bits of
information that tell the cell how to function, much the same way the
information that comes in through our eyes, ears, nose, mouth and skin
tells us how to function.

“To really understand how one cell becomes totipotent [a stem cell] and
then becomes something else, you need to know how it integrates in an
organism,” Miglietta said. Yamanaka and a collaborator pointed out that
same problem in a recent paper. They said if we really want to understand
the fates of cells, we’d be wise to study an organism that already has a
mechanism for creating stem cells from mature cells: Turritopsis.

So that’s what Miglietta and Piraino are doing. They have collected medusas
and polyps of Turritopsis and are looking at which genes are active in
de-aging, paying particular attention to the pieces of protein Yamanaka
identified that have the power to turn mature mouse skin cells back into
stem cells. Miglietta listed the questions they hope to answer.

“We want to understand the role of the [Yamanaka] genes in Turritopsis,”
she said. “Are they there? Are they not? And if there are only two or three
genes, what is the role of each of these factors? And can we use
Turritopsis as a model system to understand the behavior of the genes?
That’s where we are going.”

But until the data are crunched and the experiments are replicated, the
secret to immortality remains the mystery it has always been.